Thymopentin-loaded phospholipid-based phase separation gel with long-lasting immunomodulatory effects: in vitro and in vivo studies

Abstract

Thymopentin (TP5) is an effective immunomodulatory agent for autoimmune disease that has been used clinically for decades. However, its application is greatly limited by its extremely short half-life in vivo, poor membrane permeability and extensive metabolism in gastrointestinal tract, resulting in repeated injection and poor patient compliance. In the present study, we developed a TP5-loaded, phospholipid-based phase separation gel (PPSG) to achieve sustained drug release profile and long-lasting therapeutic effects. We firstly demonstrated the physiochemical characteristics of PPSG before and after phase transition by examining the viscosity and morphology change caused by the phase transition. Moreover, the PPSG exerted a low cytotoxicity in L929 cells and HUVECs, suggesting the biocompatibility of PPSG. A month-long drug release profile of TP5 PPSG was observed both in vitro and in vivo, revealing its sustained and controlled drug release property. Most importantly, in cyclophosphamide-induced immunosuppressive rats, a single dose of TP5 PPSG (15 mg/kg, sc) injected could normalize their T-SOD levels and CD4+/CD8+ ratio; such an immunoregulatory effect was comparable to that produced by repeated injection of TP5 solution (0.6 mg/kg per day, sc) for 14 consecutive days. Thus, TP5 PPSG has a great potential for sustained delivery of TP5 in clinical use because of its simple manufacture process, good biocompatibility and long-lasting immunomodulatory efficacy, which could greatly improve patient compliance.

Supramolecular Nanofibrils Formed by Coassembly of Clinically Approved Drugs for Tumor Photothermal Immunotherapy

“…[ 9 ] Accordingly, herein, we coassembled immunomodulatory thymopentin (TP5) and indocyanine green (ICG) to form nanofibrils (TP5‐ICG NFs) for localized combinatorial NIR photothermal immunotherapy for pancreatic tumors. Of note, TP5 has been used clinically for decades as an effective immunomodulatory agent that alters the function of mature T cells, [ 10 ] and it also possesses hydrogen binding sites for the regulation of ICG molecules to form long‐range ordered‐fibril nanostructures that alleviate intermolecular aggregation while retaining the original capabilities of fluorescence imaging and photothermal conversion. Additionally, the high aspect ratio of the fibril nanostructures showed more obvious retention in tumor tissue than other nanostructures, such as nanospheres, which are favored for localized injection.…”

rhCNB Improves Cyclophosphamide-Induced Immunodeficiency in BALB/c Mice

“…All these suggest that rhCNB can promote the production of immune cells in the body with low immune function, thus enhancing the immune function. By suppressing the activity of monocytes and macrophages, cyclophosphamide can prevent T lymphocytes and B lymphocytes from proliferating and differentiating [25][26][27][28]. Additionally, cyclophosphamide can affect cytokine production by activating the NF-κB pathway by affecting signaling pathways such as dendritic cells, TLR 2 , and TLR 4 [29].…”

Targeting the TLR2 Receptor With a Novel Thymopentin-Derived Peptide Modulates Immune Responses

“…TP5, a parental peptide of the hybrid peptide CbTP, is an effective immunomodulatory agent for immunodeficiencyrelated diseases that has been used clinically for decades. However, its application is greatly limited by its extremely short half-life in vivo, resulting in repeated injection and poor patient compliance (20)(21)(22). In view of the half-life of peptides significantly affecting the dosage and therapy, it becomes an important task to prevent rapid degradation and prolong the half-life of such drugs.…”

“…TP5 is a potent immunopotentiator and plays an important role in the process of immune enhancement. However, the fairly short half-life of TP5 greatly reduces its pharmacological potential for immunosuppression therapy (20)(21)(22). Although CATH2 has a long half-life, it shows relatively limited immunoregulatory activity and some cytotoxicity toward eukaryotic cells, which seriously hampers its clinical development (15).…”